CN108840863A - A kind of tetrahydrofuran substituted uracil kind compound that treating liver cancer and its pharmaceutical composition and application - Google Patents
A kind of tetrahydrofuran substituted uracil kind compound that treating liver cancer and its pharmaceutical composition and application Download PDFInfo
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- CN108840863A CN108840863A CN201810581564.7A CN201810581564A CN108840863A CN 108840863 A CN108840863 A CN 108840863A CN 201810581564 A CN201810581564 A CN 201810581564A CN 108840863 A CN108840863 A CN 108840863A
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- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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Abstract
The present invention provides a kind of tetrahydrofuran substituted uracil kind compound for treating liver cancer and its pharmaceutical composition and application, the tetrahydrofuran substituted uracil kind compound has such as following formula A chemical structure：
Description
Technical field
The present invention relates to pharmaceutical technology fields, specifically, the present invention relates to a kind of tetrahydrofuran substitutions for treating liver cancer
Uracil compounds and its pharmaceutical composition and application.
Background technique
Malignant tumour (cancer) is the major disease of the mankind, and the research and development for reinforcing new type antineoplastic medicine has very
Important meaning.The existing malignant tumor patient in the whole world is more than 22,000,000 people, newly examines patient every year up to 10,100,000 people, dies of every year swollen
Tumor is more than 6,200,000.At least 300 to 4,000,000 people of the existing malignant tumor patient in China, newly examining patient every year is more than 1,600,000 people, year
Death toll is more than 1,300,000.With extension, dietary structure and the environment of fast development, the average life span of China's economy and society
The change of factor, tumor incidence and the death rate are in trend is risen rapidly, and great change also has occurred in spectrum of disease, at present in rural area
Regional population's tumour occupies cause of the death third position (107.1/10 ten thousand people), and has ranked first place (126.0/10 in the urban population cause of the death
Ten thousand people).Operation, radiation and chemotherapy are the conventional therapy means of tumour.Operation, radiotherapy are suitable only for the tumour locally occurred；It is right
The Advanced cancers shifted, cytotoxic chemotherapy agents are still first-line treatment scheme；However, for a long time, routinizing
Drug big, the patient's poor resistance that always exists toxic side effect is treated, the problems such as long-time service causes drug dependence etc.；And some pairs are changed
The insensitive tumor type of drug is treated, patient is also in the state to past medical help.Therefore, exploitation low toxicity, efficient and cancer target
The anticancer therapy technology of property characteristic, becomes the emphasis of current research and treatment.
The disease incidence of liver cancer has increase trend in the world in recent years, occupies the 5th of malignant tumour, death rate position
Occupy the 3rd of malignant tumour.China is the high-incidence country of liver cancer, and liver cancer case accounts for about the 55% of the whole world, and the death rate is only second to lung
Cancer occupies second.Clinical practice shows that most liver cancer patients fail early detection, early diagnosis and targetedly treat in early days
And the postoperative high transfer and relapse of HCC results in that HCC totality prognosis is still very poor, 5 years total survival rates are only 3%-5%.Operation
Excision is the prefered method of current HCC, but there still have the patient of 60%-70% transfer occur in HCC radical excision postoperative 5 years to be multiple
Hair, and most of tumour patients ultimately succumb to metastases and recurrence.Sorafenib is the treatment liver cancer of currently the only listing
Small molecule target therapeutic agent, using antiangiogenesis therapy as dominant mechanism, but Sorafenib shows advanced liver cancer and controls
While therapeutic effect, the absolute value of patient's median survival interval was extended less than 3 months, and some researches show that such molecular targeted
Drug while inhibiting tumour growth, have and promote the side effects such as metastases, therefore, further find new effective liver cancer
Molecular targeted therapy, particularly anti-liver cancer and anti-diversion medicaments extend patient's existence, particularly progressive stage patient to further
Existence improves patient's prognosis with important scientific meaning and application value realistic.
Tetrahydrofuran substituted uracil kind compound can play the role of interference, antagonism, energy in human body to tumour cell
Interference, the synthesis of antagonism DNA, RNA and protein, and the duration is long, function and effect are obvious, anticipate with important biological study
Justice.
Status based on the prior art, the quasi- tetrahydrofuran substituted uracil kind compound that provides of present inventor are being controlled
Treat the effect in liver cancer, and in particular to a kind of tetrahydrofuran substituted uracil kind compound for treating liver cancer and its pharmaceutical composition
With application.
Summary of the invention
In view of the above-mentioned problems, the present invention provides a kind of tetrahydrofuran substituted uracil kind compound for treating liver cancer and its
Pharmaceutical composition and application, synthetic route is short, and process conditions are mild, is not necessarily to high temperature, and Atom economy is high, only a small amount of waste material row
It puts, embodies the theory of Green Chemistry well, purity is high；And inhibitory activity with higher, tumour can be interfered thin in vivo
The synthesis of born of the same parents DNA and its protein can more significantly inhibit in the Lung metastases and liver of liver cancer to inhibit the tumor formation and growth of liver cancer
It sends out.
It is described it is an object of the present invention to provide a kind of tetrahydrofuran substituted uracil kind compound for treating liver cancer
Tetrahydrofuran substituted uracil kind compound has such as following formula A chemical structure：
,
Wherein R is、、、、
Or, X is、Or；
* C atom adjacent is bonding atom in R, and the carbon atom on R and tetrahydrofuran ring is covalently attached, the adjacent F atom of *, Cl in X
Atom, Br atom are bonding atom, and the carbon atom on X and uracil ring is covalently attached.
It is another object of the present invention to provide a kind of tetrahydrofuran substituted uracil kind compounds for treating liver cancer
The synthesis step of preparation method, the tetrahydrofuran substituted uracil kind compound is：
；
Firstly, methanol is placed in cryogenic thermostat reactive bath technique, it is passed through hydrogen chloride gas, the methanol solution of hydrochloric acid is prepared, as acid
Agent；
It is stirred in acidification agent solution secondly, compound B is added to and is filled, heating water bath is reacted to being kept the temperature after 28-35 DEG C
5-6h, HPLC monitoring reaction terminate, and are cooled to 15 DEG C after reaction, filter, obtain compound C, solution is concentrated back after suction filtration
Receive methanol；
Finally, under nitrogen protection, compound C is added in compound D, catalyst and alkali, heating, after reacting 3-5h is added
Filtering, is spin-dried for solvent, and the aqueous solution that methanol is added continues to heat 4-6h, and HPLC monitoring reaction terminates, and dehydrated alcohol recrystallizes
To compound A, i.e. tetrahydrofuran substituted uracil kind compound.
Specifically, the catalyst is carbon tetrachloride, carbon tetrabromide, bromo trichloromethane, dichloroethanes or the tertiary fourth of peroxide
Alcohol.
Specifically, the alkali is sodium hydroxide, potassium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide.
Specifically, the temperature after the heating is 80-120 DEG C.
It is another object of the present invention to provide a kind of tetrahydrofuran substituted uracil kind compounds for treating liver cancer
Pharmaceutical composition, described pharmaceutical composition include a effective amount of formula A and pharmaceutically acceptable carrier,
,
Wherein R is、、、、
Or, X is、Or；
* C atom adjacent is bonding atom in R, and the carbon atom on R and tetrahydrofuran ring is covalently attached, the adjacent F atom of *, Cl in X
Atom, Br atom are bonding atom, and the carbon atom on X and uracil ring is covalently attached.
Specifically, the pharmaceutically acceptable carrier be filler or solubilizer, adhesive, moisturizer, disintegrating agent, delay it is molten
One of agent, absorbsion accelerator, wetting agent, adsorbent, lubricant, PH regulator are a variety of.
Specifically, described pharmaceutical composition is capsule, tablet, powder, pill, granule or injection.
It is another object of the present invention to provide the tetrahydrofuran substituted uracil kind compound formula A in treatment liver cancer
In application,
Wherein R is、、、、
Or, X is、Or；
* C atom adjacent is bonding atom in R, and the carbon atom on R and tetrahydrofuran ring is covalently attached, the adjacent F atom of *, Cl in X
Atom, Br atom are bonding atom, and the carbon atom on X and uracil ring is covalently attached.
The method of application of the not no pharmaceutical composition to formula A or comprising formula A of the present invention is particularly limited, representative to apply
Include with mode（But it is not limited to）：Oral, parental injection, local administration.
Solid dosage forms for oral administration includes capsule, tablet, powder, pill, granule.In these solid dosage forms
In, formula A is mixed at least one Conventional pharmaceutical carriers, is such as mixed with following compositions：（a）Filler, for example, starch, lactose, sucrose,
Glucose, mannitol and silicic acid；（b）Adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone,
Sucrose and Arabic gum；（c）Moisturizer, such as glycerol；（d）Disintegrating agent, such as agar, calcium carbonate, potato starch or cassava
Starch, alginic acid, certain composition silicates, sodium carbonate；（e）Retarding solvent, such as paraffin；（f）Absorbsion accelerator, such as quaternary amine chemical combination
Object；（g）Wetting agent, such as cetanol and glycerin monostearate；（h）Adsorbent, such as kaolin；（i）Lubricant, for example, it is sliding
Stone, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate.In capsule, tablet and pill, dosage form can also
Include buffer.
Liquid dosage form for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion
Liquid, suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.Suitable is aqueous
It include water, ethyl alcohol, polyalcohol and its suitable mixture with nonaqueous carrier, diluent, solvent or excipient.
Gastrointestinal administration preparation and injection drug-delivery preparation are presently the most common administration form, and experimental implementation side
Just, used effect experiment mode is not offered as administration form and is only limitted to this present invention in a specific embodiment, this field skill
Art personnel can drug according to the present invention physicochemical properties, in conjunction with the actual needs of Modern preparations technology and sufferer, by it
The several formulations such as injection, scalp absorbable preparation, implantation preparation are prepared into, to expand its administration route, and improve medicine target
Tropism effectively avoids unnecessary toxic side effect.
Obviously, above content according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Compared with the existing technology, the present invention has the advantage that：
1, the present invention is tetrahydrofuran substituted uracil kind compound, and inhibitory activity with higher can interfere tumour in vivo
The synthesis of cell DNA and its protein can more significantly inhibit Lung metastases and the liver of liver cancer to inhibit the tumor formation and growth of liver cancer
Inside send out.
2, the organic solvent that the present invention passes through hydrochloric acid（Methanol）As acidulant, organic solvent can be recycled after reaction
It recycles, solves and generate a large amount of concentrated acid wastewater problems, prevent to improve resource utilization while environmental pollution；Furthermore this hair
It is monitored in bright reaction by HPLC, improves reaction efficiency, stable yield is a kind of green with preferable popularization and application foreground
Chemical synthesis process.
3, raw material of the present invention is cheap and easy to get, and synthetic route is short, and process conditions are mild, is not necessarily to high temperature, Atom economy is high, only
A small amount of trash discharge also embodies the theory of Green Chemistry well, purity is high.
Specific embodiment
The present invention is described below in more detail to facilitate the understanding of the present invention.
It is worth noting that, those skilled in the art will realize that：Chemical reaction described in the invention can be used
Suitably prepare many other compounds of the invention, and other methods for the preparation of the compounds of the present invention are considered to
It is within the scope of the present invention.For example, the synthesis of the compound of those non-illustrations can be successfully affiliated according to the present invention
The technical staff in field is completed by method of modifying, such as protection interference group appropriate, by being removed using other known reagent
It is described in the invention, or reaction condition made into some conventional modifications.In addition, reaction or known disclosed in this invention
Reaction condition is also admittedly suitable for the preparation of the other compounds of the present invention.
Embodiment 1
1-[（3- methyl）Tetrahydrofuran -2- base] -5 FU 5 fluorouracil synthesis.
Synthesis step is：
；
Firstly, methanol (550g) is placed in cryogenic thermostat reactive bath technique, it is passed through hydrogen chloride gas body weight gains extremely（600g）Stop ventilation,
The methanol solution for preparing hydrochloric acid, as acidulant；
Secondly, by 2- methoxyl group -5 FU 5 fluorouracil（Compound B）（45g）It is added to fill and be stirred in acidification agent solution, water-bath adds
Heat reacts 6h to being kept the temperature after 35 DEG C, and HPLC monitoring reaction terminates, is cooled to 15 DEG C after reaction, filters, obtain 5- fluorine
Uracil（Compound C）（40.57g）, solution concentration and recovery methanol after suction filtration；
Finally, under nitrogen protection, by 5 FU 5 fluorouracil（Compound C）（40.57g）It is added to 3- methyltetrahydrofuran（Chemical combination
Object D）（42g）In, carbon tetrabromide is added（80ml）With sodium hydroxide（4.1g）, 80 DEG C are heated to, filters, is spin-dried for molten after reacting 5h
Agent, the aqueous solution that methanol is added continue to be heated to 80 DEG C and keep 6h, and HPLC monitoring reaction terminates, and dehydrated alcohol is recrystallized to give
1-[（3- methyl）Tetrahydrofuran -2- base] -5 FU 5 fluorouracil（Compound A（1））（77.21g）, yield 95.1%.
Embodiment 2
1-[[3-（1- chloro isopropyl -2- base）] tetrahydrofuran -2- base] and -5 FU 5 fluorouracil synthesis.
Synthesis step is：
；
Firstly, methanol (600g) is placed in cryogenic thermostat reactive bath technique, it is passed through hydrogen chloride gas body weight gains extremely（650g）Stop ventilation,
The methanol solution for preparing hydrochloric acid, as acidulant；
Secondly, by 2- methoxyl group -5 FU 5 fluorouracil（Compound B）（50g）It is added to fill and be stirred in acidification agent solution, water-bath adds
Heat reacts 5h to being kept the temperature after 30 DEG C, and HPLC monitoring reaction terminates, is cooled to 15 DEG C after reaction, filters, obtain 5- fluorine
Uracil（Compound C）（46.78g）, solution concentration and recovery methanol after suction filtration；
Finally, under nitrogen protection, by 5 FU 5 fluorouracil（Compound C）（46.78g）It is added to 3-（1- chloro isopropyl）Tetrahydro furan
It mutters（Compound D）（48.5g）In, dichloroethanes is added（120ml）With potassium carbonate（4.5g）, 100 DEG C are heated to, after reacting 3-5h
Filtering, is spin-dried for solvent, and the aqueous solution that methanol is added continues to be heated to 120 DEG C and keeps 4h, and HPLC monitoring reaction terminates, anhydrous second
Alcohol is recrystallized to give 1- [[3-（1- chloro isopropyl -2- base）] tetrahydrofuran -2- base] -5 FU 5 fluorouracil（Compound A（2））
（86.2g）, yield 96.3%.
Embodiment 1 in the present invention, the final products in embodiment 2（Tetrahydrofuran substituted uracil kind compound）Yield
Respectively 95.1%, 96.3%, yield is very high.
According to 1 synthetic method of embodiment, the following compound i.e. compound of embodiment 3- embodiment 18, embodiment are synthesized
The compound that 3- embodiment 18 finally respectively obtains（Tetrahydrofuran substituted uracil kind compound）Chemical structure is formula A（3）Formula
A（18）；
Embodiment 3- embodiment 18 is formula A（3）Formula A（18）Compound chemical structure see the table below with chemical name.
The compound A that embodiment 1 is obtained（1）It is prepared into pharmaceutical composition, i.e. injection.
Tetrahydrofuran substituted uracil kind compound of the present invention is detected to the antitumor action of mouse below by experiment.
After 12 are immunized greatly normal Balb/c mouse anesthesia for 6-8 weeks, operative incision abdominal cavity, and liver median lobe is exposed,
10ulPBS is included 5 × 10 with micro syringe under direct-view6Murine hepatocarcinoma cell system ML-1 be injected into liver median lobe,
Electric knife closed injection hole is used after injection, is then shut off abdominal cavity.Abdomen is opened after a week confirms 100% mouse liver tumor formation effect.
The method that 48 Balb/c mouse describe according to above-mentioned experiment, the liver cancer mouse in situ for establishing ML-1 cell inoculation are real
The property tested animal model.7 days after operation, mouse is divided into five groups by randomness, every group of 12 mouse, wherein one group is control group,
Yu Si group is experimental group, and gives intraperitoneal injection A respectively to remaining four groups（1）Pharmaceutical composition.30 days after treatment, every group with
Machine extracts 4 mouse extraction tumor tissues out and weighs；Remaining mouse continues administration observation, does survival research after 80 days.
As the result is shown：30 days after the treatment, experimental group A（1）The weight of tumor tissues is 180mg in pharmaceutical composition, and
Tumour is without transfer；The weight of tumor tissues is 540mg in control group, and tumour occurs transfer and spreads；It is right after the treatment after 80 days
All dead according to group mouse, remaining four groups of mouse still survives.This illustrates A（1）Pharmaceutical composition significantly suppresses hepatocyte in situ and connects
The growth of kind tumour, and the transfer and diffusion of tumour are significantly suppressed, further relate to tetrahydrofuran substituted uracil of the present invention
Class compound has the function for the treatment of liver cancer.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention has appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.Any label in claim should not be construed as limiting the claims involved.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solution in each case study on implementation may also be suitably combined to form those skilled in the art
The other embodiments that member is understood that.
Claims (9)
1. a kind of tetrahydrofuran substituted uracil kind compound for treating liver cancer, which is characterized in that the tetrahydrofuran replaces urine
Pyrimidines have such as following formula A chemical structure：
,
Wherein R is、、、、Or, X is、Or；
* C atom adjacent is bonding atom in R, and the carbon atom on R and tetrahydrofuran ring is covalently attached, the adjacent F atom of *, Cl in X
Atom, Br atom are bonding atom, and the carbon atom on X and uracil ring is covalently attached.
2. a kind of preparation method for the tetrahydrofuran substituted uracil kind compound for treating liver cancer, which is characterized in that the tetrahydro
The synthesis step of furans substituted uracil kind compound is：
；
Firstly, methanol is placed in cryogenic thermostat reactive bath technique, it is passed through hydrogen chloride gas, the methanol solution of hydrochloric acid is prepared, as acid
Agent；
It is stirred in acidification agent solution secondly, compound B is added to and is filled, heating water bath is reacted to being kept the temperature after 28-35 DEG C
5-6h, HPLC monitoring reaction terminate, and are cooled to 15 DEG C after reaction, filter, obtain compound C, solution is concentrated back after suction filtration
Receive methanol；
Finally, under nitrogen protection, compound C is added in compound D, catalyst and alkali, heating, after reacting 3-5h is added
Filtering, is spin-dried for solvent, and the aqueous solution that methanol is added continues to heat 4-6h, and HPLC monitoring reaction terminates, and dehydrated alcohol recrystallizes
To compound A, i.e. tetrahydrofuran substituted uracil kind compound.
3. a kind of preparation method of tetrahydrofuran substituted uracil kind compound for treating liver cancer according to claim 2,
It is characterized in that the catalyst is carbon tetrachloride, carbon tetrabromide, bromo trichloromethane, dichloroethanes or tert-Butanol peroxide.
4. a kind of preparation method of tetrahydrofuran substituted uracil kind compound for treating liver cancer according to claim 2,
It is characterized in that the alkali is sodium hydroxide, potassium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide.
5. a kind of preparation method of tetrahydrofuran substituted uracil kind compound for treating liver cancer according to claim 2,
It is characterized in that the temperature after the heating is 80-120 DEG C.
6. a kind of pharmaceutical composition for the tetrahydrofuran substituted uracil kind compound for treating liver cancer, which is characterized in that the medicine
Compositions include a effective amount of formula A and pharmaceutically acceptable carrier,
,
Wherein R is、、、、
Or, X is、Or；
* C atom adjacent is bonding atom in R, and the carbon atom on R and tetrahydrofuran ring is covalently attached, the adjacent F atom of *, Cl in X
Atom, Br atom are bonding atom, and the carbon atom on X and uracil ring is covalently attached.
7. a kind of pharmaceutical composition of tetrahydrofuran substituted uracil kind compound for treating liver cancer according to claim 6
Object, which is characterized in that the pharmaceutically acceptable carrier be filler or solubilizer, adhesive, moisturizer, disintegrating agent, delay it is molten
One of agent, absorbsion accelerator, wetting agent, adsorbent, lubricant, PH regulator are a variety of.
8. a kind of pharmaceutical composition of tetrahydrofuran substituted uracil kind compound for treating liver cancer according to claim 6
Object, which is characterized in that described pharmaceutical composition is capsule, tablet, powder, pill, granule or injection.
9. tetrahydrofuran substituted uracil kind compound according to claim 1, which is characterized in that the tetrahydrofuran takes
The application in liver cancer is being treated for uracil compounds formula A,
Wherein R is、、、、
Or, X is、Or；
* C atom adjacent is bonding atom in R, and the carbon atom on R and tetrahydrofuran ring is covalently attached, the adjacent F atom of *, Cl in X
Atom, Br atom are bonding atom, and the carbon atom on X and uracil ring is covalently attached.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107235967A (en) * | 2017-07-27 | 2017-10-10 | 福州大学 | The synthesis technique of antineoplastic Tegafur |
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| CN107235967A (en) * | 2017-07-27 | 2017-10-10 | 福州大学 | The synthesis technique of antineoplastic Tegafur |
| CN107963994A (en) * | 2018-01-22 | 2018-04-27 | 精华制药集团南通有限公司 | A kind of green method for preparing 5 FU 5 fluorouracil |
-
2018
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| JPS53144585A (en) * | 1977-05-23 | 1978-12-15 | Asahi Chem Ind Co Ltd | Novel uracil derivative and process for its preparation |
| CN105412943A (en) * | 2015-09-25 | 2016-03-23 | 徐州医学院 | Nano particle composition and anti-tumor application thereof |
| CN107235967A (en) * | 2017-07-27 | 2017-10-10 | 福州大学 | The synthesis technique of antineoplastic Tegafur |
| CN107963994A (en) * | 2018-01-22 | 2018-04-27 | 精华制药集团南通有限公司 | A kind of green method for preparing 5 FU 5 fluorouracil |
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| Title |
|---|
| CAS: "RN：1242248-57-2", 《REGISTRY数据库》 * |
| MICHEL PRE´VOST，等: "Synthesis of 1’,2 ’-cis-Nucleoside Analogues: Evidence of Stereoelectronic Control for SN2 Reactions at the Anomeric Center of Furanosides", 《J. AM. CHEM. SOC.》 * |
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| CN107235967A (en) * | 2017-07-27 | 2017-10-10 | 福州大学 | The synthesis technique of antineoplastic Tegafur |
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